Highly Purified Eicosapentaenoic Acid Improves Decreased Toe-Brachial Index in Japanese Patients with Type 2 Diabetes Mellitus

[4]. The ratio of plasma EPA to Arachidonic Acid (AA) has been reported to be significantly decreased in patients with PAD, indicating that a reduced ratio of plasma EPA/AA may be involved in the development of peripheral arteriosclerosis in these patients [5]. Highly purified EPA has been reported to significantly reduce brachial-ankle pulse wave velocity in patients with cardiovascular risk factors [6] or Type 2 Diabetes Mellitus (T2DM) [7]. However, whether highly purified EPA improves peripheral microcirculation in the toes of diabetic patients with obliterating arteriosclerosis has not yet been investigated. The present data demonstrate a possible improvement of peripheral microcirculation with administration of highly purified ethyl eicosapentaenoate in the big toes of patients with T2DM who have a decreased blood supply in the foot.


Introduction
Disturbance of peripheral microcirculation in the lower limbs of diabetic patients is associated with skin ulcer and/ or foot gangrene [1].A diagnosis of Peripheral Artery Disease (PAD) indicates a high risk of amputation in diabetic patients, but amputation of a lower limb worsens the quality of life of these patients.Improved peripheral microcirculation in the foot should effectively prevent the risk of amputation.
Fish oil, which is rich in n-3 Polyunsaturated Fatty Acid (PUFA), contains a property that prevents the development of atherosclerosis and thrombosis [2].Dietary supplementation with n-3 PUFA has been reported to improve decreased Ankle-Brachial Index (ABI) in patients with PAD [3].Eicosapentaenoic acid (EPA), which is an important PUFA in fish oil, improves blood coagulability and prevents the development of thrombosis

Statistical analysis
All data are expressed as mean ± SD.Statistical analysis was performed by using Prism Version 4.0b computer software.Individual comparison of the mean values before and after treatment was performed by using paired Student t test.P < 0.05 was considered statistically significant.

Results
After treatment with ethyl eicosapentaenoate for 4 weeks, 10 patients had a significant decrease in TBI of both the right and left big toes and 15 patients had a significant decrease in TBI of only a single big toe (right or left).As shown in Table 1, body weight and glycemic control did not change as a result of treatment.Decreased TSB with decreased blood flow in the big toes of these patients significantly increased from 72.8 mm Hg to 87.8 mm Hg, although brachial systolic and diastolic blood pressure did not change.Decreased TBI significantly improved from 0.48 to 0.61 and was normalized in 24 of 35 big toes (68.6%).In addition, ABI significantly increased from 1.09 to 1.13.Although the ABI was less than 0.9 in 6 of 35 lower limbs (17.1%) in the 35 patients with decreased TBI before the start of the treatment, the decreased ABI normalized in 4 of these 6 lower limbs (66.7%).

Discussion
This study showed that administration of highly purified ethyl eicosapentaenoate for 4 weeks significantly improved decreased TSB and TBI in Japanese patients with T2DM, independently of glycemic control and blood pressure in the general circulation.ABI also improved after 4 weeks of treatment.Low TSB and TBI are important risk factors for amputation [2], so improvement in TSB and TBI with administration of highly purified ethyl eicosapentaenoate should contribute to the prevention of skin ulcer and/or gangrene in the feet of patients with T2DM who have PAD.
The EPA/AA ratio has been reported to be significantly lower in patients with PAD [6], but administration of highly purified ethyl eicosapentaenoate significantly increases this ratio [10].We have previously demonstrated a significant reduction of plasma thrombin-antithrombin III complex with administration of ethyl eicosapentaenoate for 4 weeks in patients with T2DM who have albuminuria [11].The present data showed that the effect of ethyl eicosapentaenoate on peripheral circulation in the toes is apparent after only 4 weeks of treatment.Therefore, an improvement in hypercoagulability with use of highly purified ethyl eicosapentaenoate contributes to improvement of peripheral circulation in big toes.Furthermore, the Japan EPA Lipid Intervetion Study (JELIS) showed that treatment with ethyl eicosapentaenoate markedly reduced the occurrence of coronary artery disease in patients with PAD [12].It is supposed that administration of highly purified ethyl eicosapentaenoate is beneficial in patients with T2DM who have PAD.
In conclusion, highly purified ethyl eicosapentaenoate improves peripheral microcirculation in the toes of patients with T2DM who have decreased TBI, independently of glycemic control and blood pressure.Administration of highly purified ethyl eicosapentaenoate is beneficial in preventing the development of gangrene and avoiding amputation because of gangrene in patients with T2DM who have PAD.

Table 1 :
Changes of metabolic parameters before and at 4 weeks after the start of high purity ethyl icosapentatenoate administration.
* p < 0.05; ** p < 0.01 vs. the value before the start of high purity EPA administration.Data represent mean ± SD.SBP: Systolic Blood Pressure, DBP: Diastolic Blood Pressure.